Parkinson's disease (PD) is the second most common neurodegenerative disease. Mutations in Leucine-rich-repeat-kinase 2 (LRRK2), the newly identified causative gene for PARK8 type PD with autosomal dominant inheritance, are the most prevalent genetic causes in both familial and sporadic PD. Therefore it is important to understand the mechanisms of LRRK2 mediated pathogenesis. We have generated the first transgenic mouse model for LRRK2 that recapitulated robust motor behavioral, neurochemical and pathological features of PD. These mice develop an age-dependent progressive decrease in motor activity that is responsive to treatment with levodopa. At the level of pathology, the early and most robust phenotype is the axonopathy of the nigrostriatal dopaminergic projection, accompanied by hyperphosphorylated tau. Therefore, among all the aspects of LRRK2 induced pathogenesis, the tau-mediated axonal degeneration is particularly important and worth a major effort of investigation. We will address important questions at molecular, cellular and animal model levels. Hypothesis 1: At the molecular level, LRRK2 induces tau hyperphosphorylation that mediates the pathogenic effects. Specific Aim 1: To confirm that tau is an integral component of mutant LRRK2 kinase signaling. Hypothesis 2: At the cellular level, tau mediated axonal degeneration is a critical aspect of LRRK2 PD. Specific Aim 2: To investigate whether LRRK2-induced tau hyperphosphorylation causes axonal pathology in primary neuronal cell cultures. Hypothesis 3. At the organismal level, tau-mediated axonopathy leads to dopaminergic neuronal degeneration and progressive motor deficits. Specifc Aim 3: To test the interaction of tau and LRRK2 in genetic mouse models. This set of studies will identify the molecules and the pathways in LRRK2 pathogenesis. This is not only important from a scientific point, but also critical for the therapeutic development that directly addresses a major public health issue. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is the second most common neurodegenerative disease. Mutations in Leucine-rich-repeat-kinase 2 (LRRK2) are the most important genetic causes in PD. Therefore the understanding of the LRRK2 pathogenic mechanisms is not only important from a scientific point, but also critical for the therapeutic development that directly addresses a major public health issue.